HIV-1 infection is associated with loss of CD4+ T cells, chronic immune activation and progressive immune dysfunction. HIV-specific responses, particularly those of CD4+ T cells, become impaired early after infection and the basis for this decline in function has not been fully elucidated. Regulatory T cells (Tregs), a cellular subset with constitutive immunosuppressive activity first described in the context of autoimmune disorders, are one of several cellular subsets involved in controlling inappropriate or excessive immune activation. CD25+CD4+Foxp3+ Tregs have been demonstrated to suppress antigen-specific T cell responses directed against tumors and allografts as well as against parasitic, bacterial, fungal, and viral antigens. Tregs are thought to play a prominent role in maintaining the delicate balance between an immune response that is sufficiently robust to clear the infection and the immunopathological consequences of sustained immune activation and inflammation. Recent studies in HIV-1 infection indicate that regulatory T cells contribute to HIV-induced immune dysfunction and they were shown to suppress HIV-1 specific CD4+ T cell and CD8+ T cell responses in vitro. However, whether or not the frequency of peripheral Tregs is increased in chronic HIV-infected individuals remains controversial and the exact role of Tregs in HIV-1 infection is poorly understood. Detailed studies in this evolving field of T cell regulation are needed to begin to understand the exact function of Tregs in HIV-1 infection. Methodological barriers to isolate pure Treg populations have recently been overcome. We therefore propose to perform a detailed analysis of the frequency and function of Tregs in different stages of HIV-1 infection with the hypothesis that Tregs are impaired during the chronic stage of HIV-1 infection and thus contribute to enhanced immune activation. We hypothesize that Toll-like receptor 8 mediated effects impair regulatory T cell function and thus contribute to immune activation in chronic HIV-1 infection. The following specific aims will be addressed: 1. Evaluation of regulatory T cell activity in different stages of HIV-1 infection; 2. Assessment of HIV-1-specificity of regulatory T cells in HIV-1 infection and 3. Investigation of the impact of HIV-1-encoded TLR8 ligands on the function of regulatory T cells. These studies will further our understanding of regulation of T cell immunity in HIV-1 infection and will provide important insights for potential future immunotherapeutic interventions and vaccine research. [unreadable] [unreadable] [unreadable]